Bennett & Brachman's Hospital Infections, 5th Edition

43

Healthcare-Associated Fungal Infections*

Douglas C. Chang

David B. Blossom

Scott K. Fridkin

Introduction

Over the past several decades, advances in medical and surgical therapy have changed the type of patients cared for in today's healthcare facilities. In addition, advances in immunosuppressive agents, treatments for malignancy, chemotherapeutic agents, and bone marrow, stem cell and solid organ transplantation have resulted in many immunocompromised individuals. Also, care provided in specialized units, including parenteral nutrition, broad-spectrum antimicrobials, and mechanical ventilation, have helped treat patients suffering from previously devastating diseases and provided life to neonates previously thought to be nonviable. These successes have resulted in more severely ill, immunocompromised patients who are highly susceptible to infections caused by fungi previously considered to be of low virulence or “nonpathogenic.”

Fungal infections among these patients often are severe and difficult to diagnose and treat. Fungi are eukaryotic and more complex than bacteria; an appreciation of the unique features of nosocomial fungal infections is needed among clinicians, epidemiologists, and infection control personnel (ICPs) to best implement measures to prevent these infections. This chapter reviews the epidemiology of healthcare-associated infections (HAIs) caused by fungi, including surveillance, prevention, control, advances in diagnostics, antifungal susceptibility testing, and fungal typing.

Mold

Invasive Aspergillosis

Clinical Disease and Diagnosis of Invasive Aspergillosis

In the immunocompetent person, Aspergillus spp. can cause localized infection of the lungs or sinuses. In the immunocompromised patient, however, these pathogens often cause invasive disease of the lungs or sinuses and, because of their tendency to invade blood vessels, often spread to distant organs (Table 43-1). Clinical manifestations depend somewhat on the susceptibility of the host population under evaluation. In addition, Aspergillus spp.outbreaks have involved infections of not only the upper and lower respiratory tracts (the usual portals of entry) but also the skin and postoperative sites including vascular prostheses. From an infection control standpoint, the recognition of clinically significant cultures of mold is the cornerstone of an effective strategy to detect and prevent nosocomial invasive mold infections including aspergillosis.

Diagnosis usually is suggested by compatible but nonspecific symptoms and signs in highly susceptible hosts (e.g., those with severe or prolonged neutropenia, those taking immunosuppressive medications including solid-organ transplant recipients, and those with graft versus host disease [GVHD]). Imaging studies often are essential to establishing a diagnosis. However, plain chest radiographs are nonspecific because findings compatible with

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aspergillosis overlap with other etiologies. Chest computerized tomography (CT) scan is more helpful; compatible findings by CT scan usually precede those of plain films and specific findings such as the halo sign [1] and air-crescent sign are more specific for Aspergillus spp. infection than findings on plain films [2]. In contrast, sinus, sputum, and even bronchoalveolar lavage (BAL) fluid cultures occasionally yield Aspergillus spp., but this often reflects colonization rather than infection [3]. Among patients who are bone marrow transplant recipients and those who are neutropenic, the positive predictive value of these cultures can be 75–80% [4] but is likely much less among immunocompetent patients. Positron emission tomography (PET) can prove useful for the diagnosis and staging of invasive fungal infections but currently remains a research tool [5].

TABLE 43-1 FREQUENT SITES OF INFECTIONS AND COMMON PATHOGENS FOR HEALTHCARE-ASSOCIATED INVASIVE FUNGAL INFECTIONS

Site of Infection Fungal Pathogens CVC, central venous catheter. Bloodstream (CVC-related) Candida species Rhodotorula species Trichosporon asahii Trichosporon mucoides Bloodstream (regardless of CVC) Aspergillus terreus Acremonium species Candida species Fusarium species Scedosporium species Central nervous system Aspergillus fumigatus Scedosporium species Eye Acremonium species Aspergillus species (A. fumigatus, A. nidulans, A. ustus, A. versicolor) Candida species Fusarium species Scedosporium species Zygomycetes (Rhizopus, Rhizomucor, Absidia) Gastrointestinal tract Candida species Lungs Aspergillus species (A. fumigatus, A. nidulans, A. niger, A. versicolor) Zygomycetes (Rhizopus, Rhizomucor, Absidia) Scedosporium species Skin/soft tissue Acremonium species Aspergillus species (A. fumigatus, A. nidulans, A. ustus, A. versicolor) Fusarium species Scedosporium species Zygomycetes (Rhizopus, Rhizomucor, Absidia) Sinuses Aspergillus species (A. flavus, A. fumigatus) Zygomycetes (Rhizopus, Rhizomucor, Absidia)

For any given patient, a respiratory culture growing an Aspergillus spp. can represent true disease or colonization. From a clinical standpoint, this culture needs to be evaluated in the context of the clinical signs and symptoms and supporting diagnostic evidence for invasive disease. Ultimately, the clinical diagnosis can be confirmed only by histopathologic evidence or recovery from an involved organ. Additional challenges exist from an infection control standpoint, however; the culture also could need to be evaluated in the context of possible nosocomial acquisition regardless of whether the patient is colonized or infected.

The nonspecific presentation of invasive mold infections has spurred interest in new laboratory methods for diagnosing these infections. Briefly, several categories of nonculture based tests could be useful to the clinician in diagnosing invasive mold infections, especially aspergillosis [6]. Measurement of (1,3)-beta-D (β-D) glucan in blood can be useful as a preliminary screening tool for invasive aspergillosis despite the fact that this antigen can be detected with a number of other fungi. The Food and Drug Administration (FDA) approved a commercially available test for this antigen, Fungitell™ (Associates of Cape Cod, Inc., East Falmouth, Masachusetts), for invasive fungal infections in 2004. Fungitell™ appears to be promising for detecting most medically important fungi including Aspergillus and Candida spp., but the test does not detect Zygomycetes and has limited detection of Cryptococcusspp. due to the absence or low levels of (1,3)-β-D-glucan in these fungi. In addition, research on the detection of Aspergillus DNA through polymerase chain reaction (PCR) techniques is ongoing but these techniques are currently limited to research settings.

Techniques to detect circulating galactomannan, an antigen expressed by Aspergillus spp., in serum using a commercial enzyme immunoassay (Platelia Aspergillus EIA, Bio-Rad Laboratories, Redmond, Washington) could be more frequently encountered. This serum test was FDA-approved for use in the United States for invasive aspergillosis in 2003 but is being used more extensively in Europe. This test and the (1,3)-β-D glucan assay could provide laboratory evidence needed by clinicians to determine whether to treat a patient for invasive aspergillosis, and the European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) will likely incorporate it in the next revision of the diagnostic criteria for invasive aspergillosis [7].

Despite the fact that the galactomannan assay is validated only for serum samples, specimens of other body fluids including urine, BAL, and cerebrospinal fluid, are increasingly used to detect galactomannan. Although the test often is positive (at times more often than routine culture), its use in nonserum samples is discouraged [8]. Moreover, until more experience with these types of tests is gained, the use of nonculture-based diagnostics

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as part of the infection control assessment should be avoided. Likewise, by themselves, these test results should not constitute sufficient evidence of invasive disease for surveillance purposes.

Risk Factors for Invasive Aspergillosis

Invasive mold infections, including invasive aspergillosis, usually occur in immunosuppressed persons. The groups at greatest risk remain those undergoing hematopoeitic stem cell transplant (HSCT) and those receiving cytotoxic chemotherapy.

Allogeneic HSCT recipients are at high risk for invasive aspergillosis because of disruption of mucosal barriers, delayed engraftment, GVHD, and the use of steroids and broad-spectrum antibacterial agents [9,10,11,12]. During the early period after transplant, neutropenia due to the conditioning regimen is the major risk factor for fungal infection whereas immunosuppressive therapy for GVHD is the major risk factor during the postengraftment period [13]. Solid organ transplant recipients are other patients at risk for invasive aspergillosis. The percent of solid organ transplant recipients developing invasive aspergillosis is highest among lung recipients (6–13%), the next highest among heart and liver transplant recipients (1–8%) [14,15,16,17], and the lowest among kidney recipients [18].

ICPs should be mindful that other immunosuppressed patients also are at risk for invasive aspergillosis: Those with chronic lung diseases (i.e., chronic obstructive pulmonary disease), acquired immunodeficiency syndrome (AIDS), chronic granulomatous disease, and other hereditary immunodeficiency syndromes as well as those taking immunosuppressive medications such as corticosteroids. There have been recent reports of invasive aspergillosis in patients receiving infliximab, an agent approved in the late 1990s for use in treating Crohn's disease and rheumatoid arthritis [19,20,21]. The extent to which infliximab or other antitumor necrosis factor (TNF) therapies increase risk of fungal infection remains to be established. In these immunosuppressed groups, as well as HSCT and solid organ transplant recipients, it could be difficult to prevent environmental exposures to mold because these patients either are managed predominantly in the community or have prolonged periods of risk in nonhospital settings.

Impact and Incidence of Invasive Aspergillosis

Aspergillus spp. infections cause substantial morbidity and mortality. A study using the U.S. National Hospital Discharge Data from the 1990s estimated that >10,000 aspergillosis-related discharges occurred annually [22]. These hospitalizations resulted in 1,970 deaths and $633.1 million in costs [22]. In addition, the excess length of stay was ~12 days and excess cost was $50,000 compared with patients without aspergillosis [22]. This large study used an administrative database and lacked the ability to determine the proportion that were HAIs. Despite advances in antifungal therapy, mortality rates reported for invasive aspergillosis remain high at 30–50% [23,24].

The incidence of invasive aspergillosis is estimated to be in the range of 5% to >20% in high-risk groups [25]. Aspergillosis has been estimated to occur after 6–11% of allogeneic HSCT [10,26,27]. Some studies suggest that the incidence of Aspergillus infection among allogeneic HSCT could have increased in the 1990s [12,26] perhaps due to more frequent use of high-risk donor sources and more intense immunosuppression. Recent data suggest diagnoses during the postengraftment period could be occurring more frequently [10,12,13,27,28,29,30,31]. Explanation for this increase in disease observed in the postengraftment period could include decreased duration of the neutropenia, increased use of HLA-mismatched transplants that increase risk for GVHD, and increased survival past the early transplant period. The risk of invasive aspergillosis among autologous HSCT is lower compared to the risk in allogeneic transplantation; reports describe incidence rates of about 1–2% [10].

Assessing the incidence of invasive aspergillosis is difficult for a variety of reasons. The lack of a consistent case definition and absence of effective surveillance mechanisms make it difficult to compare incidence rates from different studies. This problem is not unique to aspergillosis but applies to other invasive mold infections as well. With the adoption of an international consensus definition for opportunistic invasive fungal infections for multicenter clinical trials in HSCT or cancer patients, the situation could be improving [7]. Multicenter epidemiologic studies such as those coordinated by the Transplant Associated Infection Surveillance Network (TransNet) have likewise adopted these definitions, which require evidence of histopathologic or microbiologic evidence of tissue invasion to classify a patient as having “proven” disease; in the past, diagnosis of invasive aspergillosis and other invasive fungal infections could have required neither. Because these strict definitions require the use of more invasive diagnostic procedures that may not be performed in all patients, incidence estimates likely will underestimate the true burden of disease.

Differences Among Aspergillus Species

The most common species associated with infection is Aspergillus fumigatus followed by Aspergillus flavus (Table 43-1). Other species can cause disease but less commonly, including, but not limited to, A. amstelodami, A. avenaceus, A. candidus, Aspergillus carneus, A. caesiellus, A. clavatus, A. glaucus, A. granulosus, A. lentulus, A. nidulans, A. niger, A. oryzae, A. quadrilineatus, A. restrictus, A. sydowi, A. terreus, A. ustus, and A. versicolor. Some recent reports have documented a shift in pathogen profile to a profile with more nonfumigatus species of Aspergillus. One Aspergillus sp. of concern is A. terreus, which has increased or is almost as frequent as A. fumigatus in some institutions [32,33,34,35].

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Infections due to A. terreus are concerning because these isolates demonstrate in vitro resistance to amphotericin B, and these infections often respond poorly to treatment [33,34,36,37]. A. terreus has been isolated from showerheads, hospital water systems, and potted plants [38,39]. While most bloodstream isolates of Aspergillus represent pseudofungemia, A. terreus (as well as other fungi such as Fusarium, Scedosporium, and Acremonium spp.) often has caused true fungemia, so detection by recovery in blood culture often represents true disease [35,40,41,42]. The emergence of A. terreus could be due in part to improved means of laboratory recovery, altered microbial flora among patients with prior exposure to amphotericin B, and/or other unmeasured environmental factors.

Outbreaks of Aspergillus, Likely Sources, and Routes of Exposure

Infection with Aspergillus spp. requires an exposure to the fungus from the environment in a susceptible host. It often is impossible to link specific exposures to disease, especially in sporadic episodes. Regardless, an understanding of the sources and routes of exposure associated with nosocomial aspergillosis, based largely on reports from outbreak investigations, has contributed to the rational basis for development of evidence-based preventive measures (Table 43-2).

Inhalation of Aspergillus spp. conidia from contaminated air is thought to be the primary means of acquiring aspergillosis. Conidia are able to remain viable for prolonged periods of time and can be disturbed from soil, where they are commonly found, and other contaminated material dispersed into the air. Because fungal conidia are relatively small, they can be suspended in air for extended periods and subsequently inhaled by individuals. When conidia eventually settle, they can contaminate environmental surfaces in the hospital.

The best evidence implicating contaminated air as a source of exposure comes from multiple outbreaks temporally associated with demolition, renovation, and construction projects [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. These projects have been both within or adjacent to the healthcare facility. Malfunctions of hospital ventilation systems, which can allow contaminated air into patient areas, also have been implicated in the development of nosocomial fungal infections during construction [53,60,63,65,66]. A hospital ventilation system can malfunction in multiple ways due to gaps between filters and framework [60], inappropriate air pressurization allowing flow of air from dirty to clean areas [63,65], and improper maintenance of high-efficiency particulate air (HEPA) filters. Lutz et al. recently found direct contamination of an air-handling system by using a confined space video camera to identify moisture and contaminated insulating material in ductwork downstream of final filters associated with an operating theater after an outbreak of postsurgical infections [66]. Contaminated air also has been reported as a result of improperly sealed windows [50,63], use of fire-proofing material [67], presence of false ceilings [43,48,51,68,69,70], and insulating material [66,70,71].

Dust particles disturbed during demolition, renovation, and construction could subsequently contaminate other surfaces in the healthcare setting. In one Aspergillus outbreak, a fire that had destroyed a building near the hospital was thought to have dispersed conidia through an open window, contaminating a hall carpet, which was believed to be the ongoing source of infection [72]. Wound infections due to Aspergillus species have been traced to the outside of packages of dressing supplies in a central supply area that were contaminated during construction [44]. Two outbreaks of pseudofungemia associated with construction have occurred when laboratory specimens were contaminated [69,73]. In one of these pseudo-outbreaks, a breakdown in specimen-processing protocols was noted [69].

Attempts to correlate conidial air concentrations with disease or colonization have provided mixed results. One study found a correlation between incidence of invasive aspergillosis in immunocompromised patients and indoor air concentration of conidia [68]. However, two longitudinal studies found no correlation between concentration and sporadic episodes [74,75]. As a result, there is no established consensus on the safe concentration of airborne conidia [76,77].

Much debate surrounds the role of hospital water systems as a source for airborne molds, including but not limited to Aspergillus spp. [38,78,79,80]. Aspergillus spp. have been isolated from hospital and municipal water supplies in several countries including the United States [38,80,81,82,83,84]. Air sampling showing increased conidial counts after using a shower suggests that conidia present in the shower head or on the walls or floor of bathrooms can be released during showering. It also has been shown that cleaning floors in patient shower facilities in a bone-marrow transplant unit reduced mean air concentrations of molds, including Aspergillus spp. [79]. Even though inhalation of conidia-laden aerosols from water sources is plausible, potable water systems are not considered a well-recognized source for disease because the link between disease and the isolation of Aspergillus spp. conidia from water is not firmly established.

Other routes of exposure besides inhalation, such as contact transmission from contaminated fomites, are possible. Molecular strain typing supported a link between a cluster of cutaneous A. flavus infections in neonatal intensive care unit patients to contaminated adhesive tape used for umbilical catheters [85]. In addition, direct inoculation fromAspergillus spp. conidia contaminating dressing materials has resulted in a cluster of surgical and burn wound infections [44].

Other environmental sources of human infection have been less commonly reported. One study in France showed that infecting Aspergillus spp. were present in foods, such as pepper, tea, and dried soup, served in a hematology

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unit [86]. Massive contamination of spices, such as pepper, by A. flavus and A. fumigatus has been linked to infection in hospitalized neutropenic patients [87]. These infections, however, were believed to be acquired through inhalation, not ingestion. Consequently, the importance of contaminated food as a source of infection has yet to be well established.

TABLE 43-2 SELECTED PUBLISHED OUTBREAKS OF ASPERGILLUS SPP. IN HEALTHCARE FACILITIES, 1990–2005

Author (Year, Country) [Ref.] Patient Population Number Primary Site(s) Species Probable Sourcea Control Measures Recommended or Applied SSI, surgical site infection; LRTI, lower respiratory tract infection; HEPA, high-efficiency particulate air; HVAC, heating, ventilation, and air conditioning; NICU, neonatal intensive care unit. a Construction can constitute activities that include demolition or renovation. Panackal et al. (2003, US) [57] Renal transplant 7 LRTI A. fumigatus Construction Impermeable barriers, HEPA filters in HVAC system, N95 respirator use during patient transport, reduce traffic, designated elevator for construction workers Myoken et al. (2003, Japan) [277] Hematology 6 Stomatitis A. flavus Undetermined Not reported Lutz et al. (2003, US) [66] Surgical 6 SSI A. fumigatus, A. flavus Air-handling system, moist insulation Remediation of air-handling unit: remove interior insulation, coat units with fungicide, clean diffusers Pegues et al. (2002, US) [88] Transplant ICU 3 SSI, LRTI A. fumigatus Debriding and dressing wounds Disruption of wound minimized, wound covered Hahn et al. (2002, US) [278] Hematology–oncology 10 LRTI A. flavus, A. niger Contaminated wall insulation from non-BMT wing Impermeable barriers, wall insulation, decontaminated HEPA filters in non-BMT wing Oren et al. (2001, Isreal) [56] Hemeatology–oncology 10 LRTI Not reported Construction Prophylaxis with low-dose systemic and inhaled or systemic amphotericin B, patients located in special ward with HEPA-filtered air Lai (2001, US) [52] Hematology–oncology 3 LRTI A. flavus Construction? BMT unit closed for 2 weeks, air intake ducts cleaned, filters and prefilters replaced; impermeable barriers installed, alarm installed and air pressure made negative in stairwell leading to construction site, edge guards around doors to anterooms, carpeting replaced by vinyl flooring, special unit that allowed breathing filtered air during patient transport Burwen (2001, US) [46] Hematology–oncology 6 LRTI A. flavus Construction High-risk patients identified and located in rooms with HEPA or laminar airflow Thio et al. (2000, US) [127] Hematology–oncology 21 LRTI A. flavus Connected hospital with higher air pressure than unit Elective admissions stopped, plants and produce prohibited in patient rooms, doors connecting to adjacent hospital engineered to close automatically, all surfaces wet wiped or mopped, pressure relationships maximized, doors to individual patient rooms kept closed, N95 masks for neutropenic patients used during transport, windows resealed, employee entrance near construction area closed Gaspar et al. (1999, Spain) [47] Hematology–oncology 11 LRTI Not reported Construction Construction area sealed, patients relocated Tabbara and al Jabarti (1998, Saudi Arabia) [61] Cataract surgery 5 Eye infection A. fumigatus Construction Not reported Singer et al. (1998, Germany) [279] NICU 4 Skin infection A. fumigatus, A. flavus Latex finger stall attached to penis to collect urine samples from male preterms Removal of finger stalls Loo et al. (1996, Canada) [54] Hematology–oncology 36 LRTI, sinusitis A. flavus, A. fumigatus Construction Portable HEPA-filter units: walls, doors, baseboards, vents, and above false ceiling painted with copper-8-quinolinolate formulated paint; windows sealed; perforated ceiling tiles replaced with nonperforated, vinyl-faced aluminum tiles; horizontal dust-accumulating blinds replaced with roller shades; patient relocated temporarily Leenders et al. (1996, Netherlands) [280] Hematology–oncology 5 LRTI, sinusitis, eye infection, mastoiditis A. fumigatus, A. flavus No single source Policies for maintaining HEPA-filtered rooms reinforced, windows kept closed at all times Bryce et al. (1996, Canada) [44] Surgical and burn units 4 Skin infection Not reported Construction, contaminated packages of dressing supplies Construction area sealed, supply room damp dusted and vacuumed, boxes and supplies wiped with cloth with buffered bleach Tang et al. (1994, UK) [281] Renal transplant unit 2 LRTI A. fumigatus Construction Impermeable barriers Iwen et al. (1994, US) [50] Hematology–oncology 5 LRTI A. fumigatus, A. flavus Construction Multiple measures taken prior to construction, environmental monitoring with gravity air-settling plates during construction-guiding additional measures Buffington et al. (1994, US) [45] Hematology–oncology 7 LRTI A. fumigatus, A. flavus Construction HEPA filters, proper pressure relationships, physical barriers, area decontamination Tritz, Woods (1993, US) [282] Hematology–oncology 4 LRTI A. terreus, A. fumigatus Not reported Not reported Flynn et al. (1993, US) [65] Hematology–oncology; medical ICU 4 LRTI A. terreus Construction; improper air pressure relationships Positive pressure and unidirectional airflow in ICU reestablished Richet et al. (1992, US) [283] Open heart surgery 6 SSI A. fumigatus Undetermined Not reported Pla et al. (1992, Spain) [284] Liver transplant 2 SSI A. fumigatus Contaminated operating room? Not reported Loosveld et al. (1992, Netherlands) [285] Hematology–oncology 6 LRTI A. fumigatus Cracked plasterwork? Plastering renovated; HEPA filters installed in each room; cleaning procedures intensified Humphreys et al. (1991, UK) [71] General ICU 6 LRTI A. fumigatus, A. flavus Perforated metal ceiling with contaminated insulation ICU cleaned extensively, patients temporarily relocated, old ICU replaced by new ICU with enhanced ventilation system and without false ceilings Arnow et al. (1991, US) [68] Hematology–oncology; solid-organ transplant 15 LRTI A. flavus, A. fumigatus Contaminated air filters Air-handlung unit remediated, contaminated air filters removed, surfaces in patient areas damp-wiped, carpet removed Weber et al. (1990, US) [62] Hematology–oncology 18 LRTI Not reported Construction Not reported Mehta (1990, India) [286] Open heart surgery 4 Endocarditis A. fumigatus Air-handling system; broad spectrum antibiotics V filters and cooling coils scrubbed weekly, filters replaced with series of prefilters and HEPA filters, air changes increased, broad spectrum antibiotics restricted

Potted plants and flowers have been found to be contaminated with Aspergillus spp. and are suggested as sources of conidia in the air of homes and hospitals. Lass-Flor et al. recently reported that isolates from four patients infected with A. terreus were identical to isolates from in-hospital plants by molecular typing [39]. One study found that one patient could have served as the environmental source during the debridement and dressing of his wounds, causing airborne transmission and subsequent wound infection in a neighboring transplant recipient although such transmission likely extremely rare [88].

Hospital Versus Community Acquisition of Invasive Aspergillosis

Although invasive aspergillosis often manifests itself during hospitalization when patients are profoundly immunosuppressed, exposure can occur outside the hospital. The relative importance of exposures from sources within the hospital or from the community is debatable; such knowledge is important for recommending prevention and control measures appropriate for different settings. Determining whether Aspergillus spp. infections are nosocomial is difficult for several reasons, one of which is that its incubation period is unknown. Thus, there is no agreement on how to define HAI episodes, and definitions are by necessity somewhat arbitrary. For example, investigators have used 3 [89], 4 [90], and 7 days [54] after hospitalization. Paterson et al. defined an HAI as one that occurred >7 days after admission to hospital or <14 days after discharge; accordingly, more than 70% of aspergillosis episodes during a 2-year period of hospital construction at their institution was acquired outside the hospital [91]. There is further evidence that most sporadic episodes are community acquired. Among allogeneic HSCT recipients, there appears to be a shift toward later onset aspergillosis after transplantation [10,12,13,27,28,29,30,31]. These later onset episodes often develop in persons long after hospital discharge.

Molecular epidemiology has improved our understanding of where Aspergillus spp. infections are acquired. Chazalet et al. used retriction fragment polymorphism (RFLP) analysis to fingerprint >700 isolates of A. fumigatus [92]. These isolates were obtained from 70 patients with invasive aspergillosis and from their hospitals' environment. Based on the theory that the isolation of an indistinguishable strain from a patient and from the immediate hospital environment is suggestive of nosocomial acquisition, 40% of the patients evaluated in this study had an HAI. It is important to note, however, that Chazalet et al. calculated that they had sampled and typed <20% of the population of strains present in the four hospitals studied.

Zygomycosis, Including Mucormycosis

Although much less common than nosocomial Aspergillus infections, HAIs caused by other molds have been increasingly reported over the past decade [33,34,93]. The next most frequently encountered infections include the Zygomycoses, which are caused by molds of the class Zygomycetes. Similar to Aspergillus spp., Zygomycetes are found in soil and decaying organic matter worldwide. Pathogens within this class include members of the order Mucorales (which cause mucormycosis), more often of the genera Absidia, Rhizopus andRhizomucor, and are than the other genera within the order Mucorales including Cunninghamella, Apophysomyces, Saksenaea, Syncephalastrum, or Cokeromyces. Disease most often occurs in severely immunocompromised persons but can occur in persons with only diabetes or recent corticosteroid therapy. Classically, persons in diabetic ketoacidosis are susceptible to infection because the acidic environment amplifies the mold's ability to use iron. Persons on deferoxamine also are susceptible because the mold is able to access the iron bound to the deferoxamine better than the iron bound to normal hemoglobin [94]. The most common manifestations of zygomycosis are pulmonary and rhinocerebral infection, yet cutaneous infection associated with preexisting skin or soft tissue breakdown also can occur (Table 43-1).

Nosocomial cutaneous zygomycosis outbreaks, specifically with R. arrhizus and R. microsporus var rhizopodiformis, have been associated with contaminated wooden tongue depressors and elasticized adhesive bandages [95,96,97,98]. A pseudo-outbreak linked to wooden sticks used in the laboratory also has been described [99]. In a recent outbreak, there were two reports of cutaneous R. arrhizus infections at stomas, the source of which were karaya gum, a nonsterile product, used as an ostomy bag adhesive [100]. While nosocomial cutaneous infections by zygomycetes are more commonly described, there also have been reports of nosocomial pulmonary or bloodstream infections (BSIs) [101,102,103]. One outbreak of rhinocerebral and disseminated zygomycosis was associated with air handler intake vents located near a hospital heliport [104]. Mortality due to zygomycosis varies by infection site, but overall mortality has improved from 84% in the 1950s before the introduction of amphotericin B to 47% in the 1990s [105].

Voriconazole, a second-generation triazole, has become the initial therapy of choice for invasive aspergillosis since 2002 and has demonstrated appropriateness as an alternative agent to amphotericin B in patients with neutropenia and persistent fever. Voriconazole has also become an attractive option for prophylaxis in severely immunocompromised patients [24,106,107]. It is important to recognize, however, that voriconazole has poor activity against zygomycotic infections [24]. Several healthcare facilities have

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documented increases in zygomycosis since the availability of voriconazole [106,108,109,110,111]. This increase could not be entirely attributable to voriconazole but to an unrelated temporal fluctuation in the environmental reservoir or an increase over time of the patients' underlying susceptibility to infection. Marr et al. reported that twice as many transplant recipients developed zygomycosis during 1995–1999 compared to 1985–1989 [112]. Similar increases occurred for aspergillosis and fusariosis, suggesting that the increase could have more to do with patient susceptibility than selection pressure for zygomycosis.

The TransNet reported preliminary data pooled from 16 centers illustrating an increase in the number of reported zygomycosis since 2001 despite stable numbers of fusariosis and declining numbers of aspergillosis. However, these data require proper adjustment (e.g., calculation of incidence by risk categories) to reflect true trends in incidence. The question remains as to whether the rate of zygomycosis is increasing because patients are surviving longer to become infected with a zygomycete or because the microbial floras among patients are being altered. Regardless, clinicians are likely to see more episodes of zygomycosis in the coming years, particularly among recipients of transplants and patients with cancer.

Other Mold Infections

Mold infections caused by Fusarium spp., Scedosporium spp., S. apiosermum (Ps. boydii), and S. prolificans also are notable because they appear to be resistant to the polyene antifungal agents and can result in breakthrough infections in high-risk patients exposed to amphotericin B. Fusarium spp. are found in soil and can cause a range of infections in humans from superficial or locally invasive skin infections to disseminated infections involving the bloodstream, sinuses, and lower respiratory tract (Table 43-1). Although the environment outside the hospital is thought to be the reservoir for most exposures, some evidence points to the involvement of water including a hospital water distribution system [80,113]. A recent study involving 9 HSCT centers reported fungemia and skin manifestations in 44% and 75% of patients with fusariosis, respectively [114]. The most frequent species causing infections in humans includes members of the Fusarium solani spp. complex, Fusarium oxysporum spp. complex, and Fusarium moniliforme [112,114,115]. Breakthrough infections have been reported during amphotericin B therapy, to which Fusarium spp. have in vitro resistance as it appears to have triazoles. The use of voriconazole as salvage therapy has been reported with some success, but immune reconstitution should be central to therapy because persistant neutropenia is the main predictor of poor outcome [114]. Overall, the mortality rate of Fusarium infection among HSCT recipients usually exceeds 80% at 90 days after infection onset [112,114].

Scedosporium apiospermum and Scedosporium prolificans are being increasingly recognized as causes of disseminated infection, often including pulmonary and central nervous system disease (Table 43-1). The combination of a severely immunosuppressed host, a predilection for dissemination, and a lack of effective antifungal therapy results in almost universally fatal outcomes. Like A. terreus and Fusarium spp., Scedosporium prolificans is capable of adventititous sporulation (sporulation in tissue), allowing hematogenous spread and frequent dissemination. A detailed review of infections among solid organ and HSCT recipients identified dissemination in >50% of Scedosporium infections; fungemia was common and occurred in >50% of them infections [116]. Blood cultures positive for these molds among patients with leukemia or HSCT recipients should be considered clinically relevant. A review of 29 cancer patients with blood cultures positive for molds found that 80% of blood cultures from which S. prolificans or S. apiospermum was recovered represented definite or probable fungemia compared with 4% (1/24) cultures in which other fungi (Aureobasidium pullulans and Paecilomyces, Alternaria, Trichoderma, Bipolaris, and Chaetomium spp.) were recovered [117].

Although it is difficult to know whether the recent appreciation of Scedosporium spp. as a pathogen is the result of improved laboratory practices or a patient population that is more susceptible, several factors suggest the latter. Scedosporium spp. are resistant to amphotericin B. Moreover, S. prolificans are considered to be resistant to all triazoles and echinocandins, whereas S. apiospermum appears to be susceptible to extended-spectrum triazoles (e.g., voriconazole and posaconazole) [118]. Husain et al. noted that in recent years, these infections have been appearing later in the posttransplantation period (i.e., median of 6 months after transplantation) and could be related to amphotericin B or triazole prophylaxis [116]. However, prolonged survival, delays in GVHD onset, and other factors could be more important in the later occurrence of these infections. Because these infections are rare, the relative importance that increasing amounts of antifungal prophylaxis will have on their incidence is unlikely to be determined.

Environmental Sampling and Molecular Typing of Mold

Because certain molds including a variety of Aspergillus spp. are widespread and commonly found in the hospital environment, interpreting the results of environmental sampling often is difficult. Isolation of the same mold species from the patient and an environmental source could be coincidental rather than proof that the sampled environment was the source of the pathogen. Isolation of a particular

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mold species from an environmental source, therefore, is at best suggestive, and other potential environmental sources should not be immediately dismissed. Furthermore, current sampling and analytical methods often are insensitive. Thus, failure to identify a particular mold species from a specific environmental source cannot rule it out as a potential source. As a general rule, environmental cultures during an outbreak investigation can be helpful only if they are directed by epidemiologic data.

Environmental sampling can be problematic because it often is not conducted until an increase in infections has been detected. Therefore, temporal continuity and baseline concentrations to determine whether an outbreak is associated with increased exposure levels are almost always unavailable. If environmental sampling is attempted, careful consideration of a number of factors is needed, ideally in consultation with someone experienced in sampling for mold. For air sampling, these factors include characteristics of the target species that could influence the choice of appropriate sampler and analytical method, sampling period to best represent probable human exposure (e.g., minutes, hours, or days), sample volume that should be large enough to be representative but not exceed the capability of the instrument, and sampling medium [119,120]. Although attractive due to the low cost, gravity sediment methods (e.g., an open petri dish) are limited because they are not volumetric, provide qualitative rather than quantitative results, preferentially select large particles, and are less sensitive than volumetric methods [119].

Culture-based methods often underestimate variety and concentrations of molds in the air [120]. Methods to measure conidia counts that do not rely on culture also are problematic because Aspergillus conidia cannot be differentiated from Penicillium conidia and cannot be identified to the species level. In addition to air samples, samples of dust settled on surfaces and of suspected contaminated materials can be helpful. Compared to swab cultures, contact plates [119] and vacuuming methods could be preferable because they allow quantification (e.g., colony-forming units per square centimeter) and can be a good historical representation of past airborne molds because air samples collected under quiescent conditions can underestimate exposure levels due to settling.

Molecular epidemiology assumes that when several isolates are found to be genetically indistinguishable using molecular typing methods with a sufficiently high discriminatory power, they are derived from a recent common ancestor [121]. However, although molecular typing of fungi, such as Aspergillus spp., has improved, traditional epidemiological data are still needed to interpret the results. The indications for molecularly typing molds associated with invasive disease remain undefined.

Molecular typing methods designed to determine the relatedness of particular strains have improved. For Aspergillus spp., the molecular typing methods reported to have had some success include (1) isoenzyme analysis, (2) RFLP analysis, which includes restriction endonuclease analysis and hybridization with single genes, tandemly repeated genes, and dispersed repetitive DNA probes, and (3) PCR-based procedures using randomly amplified polymorphic DNA (RAPD) (also termed arbitrarily primed PCR ox[AP-PCR]), sequence-specific polymorphic DNA, and analysis of polymorphic microsatellite markers [122]. No consensus on the use of typing methods for Aspergillus spp. exists. These tests should be used in conjunction with specialty reference laboratories. Ideally, samples from nonoutbreak patients and areas of the hospital should be collected and typed together with the outbreak strains.

Surveillance for Invasive Mold Infection

Surveillance strategies for invasive mold HAIs, including aspergillosis, traditionally have focused on identifying pulmonary disease. The Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers of Disease Control and Prevention (CDC) strongly recommends taking several routine steps supported by experimental, clinical, and/or epidemiologic studies and by strong theoretical rationale. These steps include (1) maintaining a high index of suspicion for healthcare-associated invasive mold infection in severely immunocompromised patients (Table 43-3) and (2) establishing a system by which the facility's infection control personnel are promptly informed when Aspergillus spp. is isolated from cultures of specimens from a patient's respiratory tract and by periodically reviewing the hospital's microbiologic, histopathologic, and postmortem data (Table 43-3) [77]. Currently, there is good evidence that routine, periodic cultures of the nasopharynx or nares of asymptomatic patients at high risk for disease are not informative of nosocomial transmission and should be discouraged. Likewise routine, periodic cultures of equipment or devices used for respiratory therapy, pulmonary function testing, and delivery of inhalation anesthesia in the HSCT unit or of dust in rooms of HSCT recipients are discouraged.

ICP need to balance the costs of and time involved in performing ongoing surveillance with the likelihood for detecting any disease. Any ongoing surveillance usually can be limited to the high-risk population, which can change periodically as new programs are added or removed from the hospital. In addition, heightened surveillance should be encouraged during periods of potential increased exposure (e.g., during renovation, construction, and destruction). This includes expanding either the scope of baseline surveillance to include new patients (postoperative patients or those with less severe but significant immunosuppression) or new data sources (Table 43-3).

CDC and infection control staff in New Orleans outlined a strategy for a reasonable approach to detecting invasive mold infections among immunosuppressed persons during a period of extensive exposure to indoor molds in the aftermath of Hurricane Katrina [123]. These definitions were modified from the EORTC/MSG criteria and could be useful to ICP performing surveillance for invasive mold infections in healthcare settings during periods of increased

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concern or in populations at high risk for invasive mold HAIs (Tables 43-4 and 43-5). An investigation should be conducted if one or more episodes of hospital-acquired invasive mold infections are detected.

TABLE 43-3 FACTORS TO CONSIDER IN DEVISING A SURVEILLANCE STRATEGY FOR NOSOCOMIAL MOLD INFECTIONS

Surveillance Aspects Considerations µL, microliter. Patients of concern: Identify groups of patients at greatest risk for invasive mold infections Transplant recipients, including organ and hematopoietic stem cell, within 6 months of transplant and/or during periods of substantial immunosuppression Neutropenia (neutrophil count <500/µL) from any cause including neoplasm and cancer chemotherapy CD4+ lymphocyte count <200/µL from any cause including HIV infection Ongoing cancer chemotherapy, corticosteroid and other immunosuppressive drug therapy, and immunosuppressive diseases, such as leukemia or lymphoma Data sources: Consider expanding access to selected data sources during the finite period of concern (e.g., demolition) Microbiology reports should be performed at least weekly, and infection control personnel should be notified of positive results for Aspergillus spp., Fusarium spp., Scedosporium spp., Rhizopus spp.,Rhizomucor spp., and Absidia spp. or other molds isolated from culture. Because the utility of subtyping isolates to assist in ascertainment of possible healthcare-related transmission is largely determined by the epidemiology of a suspected outbreak, microbiology laboratories should retain all mold isolates known to cause invasive disease to facilitate investigations during period immediately postremediation. Histopathologic and postmortem data should be reviewed at least monthly for reports for morphological terms suggestive of an infection such as “fungal elements” or “hyphae.” If possible, chest radiographs and CT scans should be reviewed at least weekly (e.g., specialty care ward) for entries that specify findings consistent with fungal pneumonia or aspergillosis such as the halo sign, air-crescent sign, and cavity within an area of consolidation. Consider enlisting assistance of radiologist to log all patients with these findings for 6 months. Consider receiving printouts from inpatient pharmacy on all voriconazole and amphotericin-B starts if available as possible “cases.” These drugs are the most commonly prescribed for invasive mold infections and were used for candidemia as empiric therapy in 2005 less often than for mold infections. The staff of wards housing high-risk patients, such as oncology and pulmonology wards and intensive care units, should be interviewed regularly to identify patients with possible invasive mold infections. Nosocomial: When ≥1 invasive mold infection is identified, consider the following in determining whether infections are nosocomial The more characteristics present, the higher is the likelihood of the infections being acquired in the healthcare setting:  Patient was hospitalized for >2 weeks or was discharged for <2 weeks after a long hospitalization before symptoms began.  Patient had frequent hospitalizations in the preceding 6 months.  Symptoms occurred within 4 weeks of another suspected healthcare-associated mold infection.  Two suspected healthcare-associated mold infections occurred in the same area of the hospital.

Prevention and Control of Mold of Invasive Mold Infection

Several standardized approaches to eliminating exposure to indoor mold should be applied in inpatient healthcare settings. HICPAC outlines preventive measures and estimates the level of evidence-based support for each recommendation (Table 43-6, footnote a). Patient-care areas should be cleaned on a regular basis, and Environmental Protection Agency (EPA)–registered disinfectants should be used in accordance with the manufacturer's instructions to clean environmental surfaces (category IC) [76]. There is no evidence, however, that special measures, such as the use of fungicides on carpeting in general patient care areas, reduce fungal exposure (unresolved category) [76]. Similarly, there is no clear indication of the need for routinely sampling air, water, and environmental surfaces in healthcare facilities (category IB) [76]. Fungi are ubiquitous, and interpretation of fungi sampling data continues to be a challenge [124].

Because most patients are at minimal risk for invasive disease with molds and because exposures are difficult to

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prevent, preventive measures to limit mold exposure should focus on patient populations at highest risk for such disease. The CDC guidelines for preventing nosocomial pulmonary aspergillosis (Table 43-6) [77] focus on allogeneic HSCT recipients as one group of patients at high risk for respiratory exposure. The establishment of a protected environment for these patients includes providing a sealed room with ≥12 air changes per hour [125,126,127], using HEPA filtration of incoming air [56,128], and maintaining positive pressure relative to the hallway [129]. Whether similar measures to prevent exposure are required for other populations of patients, such as patients who received autologous HSCT and solid-organ transplants, remains unresolved [77].

TABLE 43-4 SURVEILLANCE DEFINITIONS OF COMMONLY ENCOUNTERED INVASIVE MOLD INFECTIONS AMONG IMMUNOSUPPRESSED PATIENTS BASED ON CRITERIA OUTLINED IN THE REVISED EORTC/MSG DEFINITIONS FOR INVASIVE FUNGAL DISEASES

Infection Site Definition EORTC/MSG, European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group; BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid. (Modified from [313]). Pneumonia (Lower Respiratory Tract Mold Infection-LRT-MI) Proven LRT-MI: Patient with EITHER 1.  Biopsy or needle aspirate of lung tissue showing histopathologic or cytopathologic evidence of hyphae and associated tissue damage 2.  Positive culture result from normally sterile site (e.g., pleural fluid, tissue) (excluding BAL, sinus cavity, urine) and that is clinically consistent with an invasive mold disease process (with or without evidence on radiograph)   Probable LRT-MI: Patient with at least ONE HOST FACTOR (Table 43-5) AND either CLINICAL CRITERIA: 1.  CT imaging showing air-crescent sign cavity, wedge-shaped infiltrate, or well-defined nodule ±, a “halo sign 2.  New nonspecific focal infiltrate and ≥1 of the following (unless microbial criteria are met): o    Hemoptysis o    Pleural rub o    Pleural pain AND at least ONE of the MICROBIOLOGIC CRITERIA 1.  Sputum or BAL culture positive for mold or direct microscopic evidence of hyphal forms 2.  Positive Aspergillus antigen from BAL or ≥1 serum samples 3.  Positive glucan assay (beta-D-glucan) ≥1 serum sample   Possible LRT-MI: Same as Probable LRT-MI except NO MICROBIOLOGIC CRITERIA, AND other potential causes have been excluded Sinonasal infection (Upper Respiratory Tract Mold Infection-URT-MI) Proven URT-MI: Patient with: 1.  Biopsy or needle aspirate of sinus tissue showing histopathologic or cytopathologic evidence of hyphae and associated tissue damage 2.  Positive culture result for a sample obtained by sterile procedure from upper respiratory tract and clinically or radiologically abnormal site consistent with infection   Probable URT-MI: Patient with at least ONE HOST FACTOR (Table 43-5) AND BOTH CLINICAL CRITERIA: 1.  Imaging studies (e.g., CT or radiograph imaging showing “erosion of sinus walls,” “extentsion of infection to neighboring structures,” or “extensive skull base destruction”) 2.  Any ONE of the following: o    Acute localized pain (especially radiating to the eye) o    Nose ulceration or eschar of nasal mucoas ± epistaxis o    Extension of paranasal sinus across bony barriers including the orbit AND the following MICROBIOLOGIC CRITERION 1.  Sinus aspirate culture positive for mold or direct microscopic evidence of hyphal elements   Possible URT-MI: Same as Probable URT-MI except NO MICROBIOLOGIC CRITERIA, AND other potential causes have been excluded. Central Nervous System Mold Infection (CNS-MI) Proven CNS-MI: Patient with EITHER 1.  Biopsy or needle aspirate of CNS tissue showing histopathologic or cytopathologic evidence of hyphae and associated tissue damage 2.  Positive culture result for a sample obtained by sterile procedure from CNS and clinically or radiologically abnormal site consistent with infection   Probable CNS-MI: Patient with at least ONE HOST FACTOR (Table 43-5) AND either CLINICAL CRITERIA: 1.  Radiographic evidence showing meningeal enhancement (i.e., CT or MRI imaging showing “meningitis extending from a perinasal, auricular, or vertebreal process”) 2.  Focal lesions on imaging of the head. AND at least ONE of the following MICROBIOLOGIC CRITERIA 1.  Non-sterile site culture (BAL, sputum) positive for mold or direct microscopic evidence of mold 2.  Positive Aspergillus antigen from BAL, pleural fluid, CSF, or ≥1 serum samples 3.  Positive glucan assay (beta-D-glucan) from ≥1 serum sample   Possible CNS-MI: Same as Probable CNS-MI except NO MICROBIOLOGIC CRITERIA, AND other potential causes have been excluded Skin Mold Infection (SKIN-MI) Proven SKIN-MI: Patient with 1.  Biopsy or needle aspirate of skin/soft tissue showing histopathologic or cytopathologic evidence of hyphae and associated tissue damage 2.  Positive culture result for a sample obtained by sterile procedure from soft tissue and clinically or radiologically abnormal site consistent with infection.   Probable SKIN-MI: Patient with at least ONE HOST FACTOR (Table 43-5) AND the following CLINICAL CRITERIA: 1.  Papular or nodular skin lesions without any other explanation AND the following MICROBIOLOGIC CRITERIA 2. Non-sterile site culture (swab, debridement, aspirate) positive for mold or direct microscopic evidence of hyphal forms   Possible SKIN-MI: Same as Probable except NO MICROBIOLOGIC CRITERIA, AND other potential causes have been excluded EYE Mold Infection (EYE-MI) Proven EYE-MI: Patient with 1.  Biopsy or needle aspirate of vitreous fluid or cornea showing histopathologic or cytopathologic evidence of hyphae and associated tissue damage, or 2.  Positive culture result from a sample of vitreous and clinically or radiologically abnormal site consistent with infection.   Probable EYE-MI: Patient with at least ONE HOST FACTOR (Table 43-5) AND the following CLINICAL CRITERIA: 1.  Intraocular findings suggesting endophthalmitis (i.e., as determined by ophthalmologic examination) AND the following MICROBIOLOGIC CRITERION 2. Non-sterile site culture (swab) positive for mold or direct microscopic evidence of hypal forms   Possible EYE-MI: Same as Probable EYE except NO MICROBIOLOGIC CRITERIA, AND other potential causes have been excluded Fungemia (BSI-MI) Proven BSI-MI: Patient with blood culture that yields a mold (e.g., Fusarium spp., Scedosporium spp.) in the context of a compatible infectious disease process (i.e., contamination has been excluded)

TABLE 43-5 HOST FACTORS FROM THE EORTC/MSG REVISED DEFINITIONS FOR INVASIVE FUNGAL INFECTIONS

EORTC/MSG, European Organization for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group. (Adapted from [313]). 1.  Recent history of neutropenia (<500 neutrophils/µL for >10 days) in previous 3 weeks 2.  Receipt of allogeneic stem cell transplant recipient 3.  Prolonged use of corticosteroids (excluding patient with allergic bronchopulmonary aspergillosis) at an average minimum dose of 0.3 mg/kg/day prednisone equivalent for >3 weeks 4.  Treatment with other recognized T-cell immune suppressants, such as cyclosporine, TNF-α blockers, specific monoclonal antibodies (alemtuzumab), nucleoside analogues during the past 90 days 5.  Inherited severe immunodeficiency (e.g., chronic granulomatous disease, severe combined immunodeficiency)

Severely immunocompromised patients, including allogeneic patients with HSCT, are at particularly high risk of acquiring Aspergillus spp. infections during periods of hospital demolition, construction, renovation, and repair [55]. Before initiating any of these projects, a multidisciplinary team including infection control staff should estimate the level of risk they will create [76]. Both the construction team and the healthcare staff in immunocompromised patient-care areas should be educated about preventive measures (category 1B) [76]. One of the most important elements of infection control is to construct barriers to prevent dust exposure. If the project is outside the hospital, windows should be sealed to prevent air intrusion (category 1B) [76]. For internal projects, the air-handling system in work zones adjacent to patient-care areas should be set to negative pressure (category 1B). Barrier materials that are impermeable to fungal spores should be used, and breaches in the barrier should be repaired [76]. In addition, pedestrian traffic should be restricted or redirected from patient-care areas. When severely immunocompromised patients need to leave their rooms (e.g., for diagnostic procedures), they should wear high-efficiency respiratory protection devices to decrease their risk of inhalation of fungal elements (category II) [77].

If a patient develops an Aspergillus spp. infection, the episode should be investigated to determine whether it is healthcare associated or community acquired. In an outbreak situation, the collection of environmental cultures can be useful. Various techniques discussed previously can be used to type the Aspergillus spp. to suggest an environmental source. In addition, ventilation deficiencies should be investigated and repaired [77].

Considerable research also is being done to decrease the severity of clinical disease from mold in high-risk patient populations. These efforts range from shortening the window of susceptibility due to neutropenia with growth factors such as granulocyte colony-stimulating factor (G-CSF) [130] to improving the early detection of mold infections [131,132]. Similarly, the role of prophylactic antifungals for patients deemed at highest risk for invasive fungal diseases, such as recipients of HSCT, is still being defined [133].

The hospital water supply remains to be established as an important source of Aspergillus spp. HAIs. As such, current HICPAC guidelines do not offer specific guidance for avoiding water exposures to prevent aspergillosis [76,77]. Some experts have proposed measures to prevent nosocomial waterborne infection with Aspergillus spp. [134]: minimizing patient exposure to tap water (e.g., using sterile water and avoiding showering) and intensively monitoring water supplies when infections occur [134]. If more evidence showing the importance of water as a source of exposure is obtained, recommendations can change.

Yeast

Candidiasis

Clinical Disease and Diagnosis of Candidiasis

The clinical manifestations of Candida spp. infections are quite variable. Although immunocompetent hosts can suffer from Candida dermatitis, oral candidiasis, and Candidavulvovaginitis, these diseases tend to be more severe in the immunosuppressed. In most circumstances,

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the presence of Candida spp. in the urine or sputum does not represent infection. Candidemia, on the other hand, almost always represents infection and is a condition with the potential for serious complications, including Candida spp. endocarditis and disseminated candidiasis.

TABLE 43-6 SUMMARY OF SELECTED PREVENTION AND CONTROL MEASURES FOR HEALTHCARE-ASSOCIATED PULMONARY ASPERGILLOSIS [77]

Recommendation Categorya ANC, absolute neutrophil count; HSCT, hematopoietic stem cell transplant; PE, protective environment; HEPA, high-efficiency particulate air filter; LAF, laminar air flow. aa Each recommendation is categorized as follows: IA-Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, epidemiologic studies. IB-Strongly recommended for implementation and supported by certain clinical or epidemiologic studies and by strong theoretical rationale. IC-Required for implementation as mandated by federal and/or state regulation or standard. II-Suggested for implementation and supported by suggestive clinical or epidemiologic studies or by strong theoretical rationale. Unresolved-Insufficient evidence or consensus regarding efficacy exists. Staff education, especially healthcare personnel about infection control procedures for aspergillus II Surveillance    Maintain high index of suspicion in immunocompromised (ANC <500/mm3 for two weeks, <100/mm3 for one week) IA  Periodically review microbiologic, histopathologic, and postmortem data II  Do not perform routine nasopharyngeal cultures of high-risk patients IB  Do not perform routine cultures of equipment in the HSCT unit IB  Determine the role of air sampling during construction or renovation unresolved  Perform surveillance of room ventilation IB New construction of specialized care units for high-risk patients    Create PE for allogeneic HSCT recipients that minimizes fungal spore counts by HEPA filtration of incoming air, directed room airflow, positive air pressure, proper seals, and high (≥12) air changes per hour IB, IC  Do not use LAF routinely in PE IB  Determine the role of PE for autologous HSCT recipients unresolved  Determine the role of PE for solid-organ transplants unresolved Existing facilities with no cases of healthcare-associated aspergillus cases    Place allogeneic HSCT recipients in appropriate PE IB   Maintain air-handling systems in PE IB, IC   Develop a water damage response plan IB   Use proper dusting method for HSCT recipients IB   Eliminate carpeting in hallways or rooms with HSCT recipients IB   Remove upholstered furniture in rooms with HSCT recipients II   Minimize time during which HSCT recipients are outside room and wear mask II   Coordinate infection control strategies with other hospital personnel IB   Eliminate flowers or plants in areas for HSCT recipients II   Develop plan to prevent aspergillus exposure during construction and renovation activities. IA   During construction, erect barriers and direct pedestrian traffic away from patient care areas IB  Determine the role of PE for autologous HSCT recipients unresolved  Determine the role of PE for solid-organ transplants unresolved Actions following a case of healthcare-associated aspergillus    Begin a retrospective review and prospective search for other cases II  Determine whether there is a ventilation deficiency IB  Do epidemiologic investigation and contact state/local health department IB  Decontaminate structural materials with antifungal biocide IB Chemoprophylaxis    Administer prophylactic antifungal by inhalation to HSCT recipients unresolved  Develop strategies to prevent recurrence of pulmonary aspergillosis in HSCT recipients unresolved

Diagnosis of a Candida spp. infection depends on the suspected site. Infections of the skin or oral or vaginal mucosa can be diagnosed by recognizing the clinical pattern and the demonstration of fungal elements on potassium hydroxide (KOH) preparation. Infections of the respiratory tract, urine, or bloodstream can be confirmed by culture. Disseminated candidiasis is diagnosed by culture of biopsy material or demonstration of Candida spp. in histologic specimens from >1 site.

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Risk Factors for Invasive Candidiasis

A variety of risk factors for candidemia exists (Table 43-7) [135]. Colonization by Candida spp. is the leading risk factor for infection in many series [135]. Colonization of multiple sites is an independent risk factor for developing invasive disease [136,137,138]. In different patient populations, including neutropenic and non-neutropenic patients, bloodstream and invasive infections could be preceded by Candida spp. colonization or superficial infection with a genotypically indistinguishable strain [139,140,141,142,143]. Approximately 5–15% of hospitalized patients is already colonized on admission; however, as exposure to risk factors for colonization accumulate during hospitalization, the percentage increases over time. Among intensive care unit (ICU) patients, it has been estimated that between 50–86% become colonized during their stay [143,144,145,146,147]. However, only a small percentage of these proceed to develop disease. Surveillance cultures are sometimes obtained, but their clinical significance is not known [144,148].

Other important risk factors include the receipt of antibiotics and/or neutropenia as well as the presence of vascular access devices. In general, the more antibiotic agents used, the broader the antibacterial spectrum, and the longer the duration of treatment, the higher is the risk of invasive candidiasis [135,138]. It is suspected that the risk is higher for cephalosporins and antibiotics with anti anaerobic activity [135,149,150,151]. Neutropenia is a well-recognized risk factor, not only for invasive candidiasis but also for other fungal infections [135,136,137,152,153]. Vascular access devices, often multiple, are required to manage ICU patients. The proportion of catheter-related candidemia ranges from 35–80% [135]. These catheters are used increasingly in non-ICU settings, including ambulatory care and home settings. Overall, it is important to note that factors associated with candidemia are no longer limited to the ICU. The diversity of elements listed in Table 43-7 highlights the extension of risk to other patient populations.

TABLE 43-7 RISK FACTORS FOR CANDIDEMIA

(Adapted from [135]). Candida colonization Surgery  From ≥1 body sites other than blood Chemotherapy  Increase >4 log in stools Steroids  Candiduria H2 blockers  Rectal swabs Multiple transfusion Antibiotics Renal failure  Prolonged use Mechanical ventilation  Multiple antibiotics  Intubation  Broadspectrum antibiotics  Duration Vascular access Increased length of stay  Arterial catheter Severity of disease  Swan-Ganz catheter  Prior bacteremia  Hickman catheter  Leukemia  Central venous catheter  Mismatched donor Bladder catheter  Acute graft-versus-host disease Neutropenia  Increased APACHE II or III score  Prolonged Low birthweight for neonates  <500/µL or <100/µL Age (>40 years; <32 weeks) Parenteral nutrition    Prolonged use    Lipid use   Antifungal prophylaxis (absence; for C. krusei, and C. glabrata vs.other strains)

Epidemiology and Impact of Canadidemia

Infections due to Candida spp. represent the most important group of fungal HAIs; they cause substantial morbidity and mortality in hospitalized patients. Candidemia is the third or fourth most common cause of bloodstream infection among hospitalized patients [154,155]. Its incidence at single centers varies greatly, ranging from 0.3 to 28 per 10,000 admissions worldwide (Table 43-8). The attributable mortality for candidemia has been estimated to be as high as 49% [156]. Data from a multicenter study from Baltimore and Connecticut measured a lower attributable mortality rate of 19–24%, depending on the patients' ages [157]. When extrapolated to the entire United States, the annual number of excess deaths due to candidemia is estimated to be 4,256–5,376, and the excess hospital costs were estimated at $44–$320 million [155].

Candidemia is not limited to the ICU, although ICU patients are at high risk secondary to the presence of

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central venous catheters and have been the focus of epidemiological study in the recent past. Data from the CDC's National Nosocomial Infections Surveillance (NNIS) system found that Candida albicans BSIs in ICUs decreased overall from more than 8 BSIs per 10,000 central venous catheter (CVC) days in 1989 to less than 3 BSIs per 10,000 CVC-days in 1999, whereas Candida glabrata BSIs increased [158]. Results of another large multicenter study involving 49 U.S. hospitals were that BSIs due to Candida spp. increased from 8% in 1995 to 12% in 2002 [154]. Further data from the U.S. National Center for Health Statistics indicate that the number of patients discharged with sepsis caused by fungi tripled from 1979 to 2000 and that candidemia was the most likely cause of fungal sepsis in hospitalized patients [159]. One possible explanation for these apparently disparate findings is that advances in medical therapy have increased the number of patients susceptible to Candida spp. BSI. Furthermore, the established risk factors for candidemia, including prior colonization, use of central venous catheters and broadspectrum antimicrobials, mucosal surface disruption (e.g., surgery, hypotension, or the presence of cytotoxins), and neutropenia are no longer limited to ICU patients (Table 43-7) [135]. In fact, a U.S. population-based study found that only one-third of patients with candidemia had disease onset in the ICU and about one-quarter was actually diagnosed before admission (although these patients could have been colonized during their previous hospitalization) [160].

TABLE 43-8 INCIDENCE OF CANDIDEMIA IN GENERAL PATIENT POPULATION REPORTS FROM SINGLE CENTERS COMPLETED 1995–2006, WORLDWIDE

Author [Ref.] Country Study Years Overall Incidence ofCandida BSI Overall C. albicans (%) Overall Mortality (%) BSI, bloodstream infections; N/A, not available. (Modified from [161]). Karlowsky et al. [287] Canada 1976–96 N/A 55.0 52.0 Luzatti et al. [288] Italy 1992–97 1.14/10,000 patient-days 54.0 45.0 Viudes et al. [289] Spain 1995–97 7.6/10,000 admissions 46.0 44.1 Malani et al. [182] United States 1988–99 N/A N/A N/A Garbino et al. [290] Switzerland 1989–2000 0.3/10,000 patient-days 66.0 44.0 Alonso-Valle et al. [291] Spain 1995–99 8.1/10,000 admissions 44.0 45.0 Hsueh et al. [292] Taiwan 1981–2000 28/10,000 discharges in 2000 50.0 60.6 [in 2000] McMullan et al. [293] Ireland 1984–2000 N/A 60.7 N/A San Miguel et al. [294] Spain 1988–2000 6/10,000 admissions 51.0 N/A Doczi et al. [295] Hungary 1996–2000 2-4.1/10,000 admissions 77.0 N/A Schelenz, Gransden et al. [187] England 1995–2001 3/10,000 admissions 64.0 35.2

A recent, comprehensive review of candidemia trends found Candida BSI to be stable in most reports during the decade spanning 1995 to 2005 in different parts of the world [161]. This finding was documented by all three survey types: general patient population from single- and multicenter surveys and specific population surveys. However, almost one-third of the reports from the general patient population indicated an increasing trend, whereas one third of the specific population reports indicated a decreasing trend [161]. This finding suggests that in these specific patient populations (e.g., ICU patients in whom the incidence of Candida BSIs often are the highest), antifungal prophylaxis measures can be showing an impact on incidence.

Four Candida spp., including C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis, account for ~95% of all Candida BSIs [160,162,163]. The remaining 5% is caused by different species, such as C. krusei, C. lusitaniae, C. guilliermondii, C. dubliniensis, C. rugosa, and others [118,164]. Reports of these unusual causes of infection are being reported increasingly and some are noted to occur in HAI clusters [165,166,167,168,169,170,171,172,173].

Candida albicans continues to be the most commonly isolated species, but the proportion of nonalbicans Candida BSIs could be increasing. In fact, nonalbicans Candida BSIs in some centers from multiple countries are now >50% [152,158,165,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194]. In some instances, this increase has been attributed to the use of azole for prophylaxis and treatment of fungal infections among certain groups of patients at high risk for Candida BSIs. Fluconazole became widely available in the early 1990s. Several reports have documented a shift in the species of Candida that cause candidemia when fluconazole use is increased [152,195]. One cancer center using fluconazole prophylaxis has reported higher numbers of C. krusei and C. glabrata in the 1990s compared with historical figures [152].

In one study of ICUs in 311 U.S. hospitals, C. glabrata BSIs per 10,000 CVC-days increased from about 0.2 in 1989 to more than 0.5 in 1999 [158]. An increase in

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1. 
   glabratainfections is concerning because the infection can rapidly acquire resistance to azoles after exposure to them [158,163]. In contrast, another large multicenter U.S. study found that percentage of C. albicansand C. parapsilosis increased from 1995 to 2002 whereas the percentage of C. tropicalis and C. glabrata decreased [154].

One factor that could influence different pathogen profiles can be geographic differences in fluconazole susceptibility in vitro among C. glabrata strains causing BSIs. For example, Pfaller et al. described geographic differences in fluconazole susceptibility trend, both internationally and within the United States; susceptibility was highest in the Asia–Pacific region (80.5%) and lowest in North America (64%) and Latin America (62.1%) [196]. Whether increased azole use is causing a shift from C. albicans remains controversial, and many variables that confound such evaluations exist.

Less Common Yeast Pathogens

A wide variety of less common yeast pathogens including Trichosporon spp., Rhodotorula spp., Pichia anomala (Candida pelliculosa), and Malassezia spp. [118,197,198,199,200,201,202,203,204,205,206,207] can cause invasive infection in an immunocompromised host. Of particular concern are opportunistic yeasts that pose challenges due to antifungal resistance [118]. Trichosporon spp. is the most commonly reported noncandidal yeast infection with reported mortality rates >80% [115,197,198,199,200,201,208,209,210,211,212,213,214,215,216,217,218,219]. Clinical failures with amphotericin B and fluconazole have been reported [115,200,201,209,216]. Isolates that are multidrug resistant to amphotericin, flucytosine, and fluconazole have been reported [219,220]. However, newer triazoles appear to be more active than fluconazole against Trichosporon spp, and successful treatment with voriconazole has been reported [209,210,219,220,221,222].

Rhodotorula spp. are emerging as important pathogens [207,223,224,225,226,227,228] Although typically a commensal of skin, nails, and mucous membranes, this species has been reported to cause fungemia, central venous catheter and ocular infections, peritonitis, endocarditis, and meningitis [207,223,224,225,226,227,228]. Clinical isolates appear to be susceptible to amphotericin B, flucytosine, and newer triazoles, but reported minimum inhibitory concentrations (MICs) for fluconazole, caspofungin, and micafungin are high [205,206,207,229].

Antifungal Susceptibility Testing of Candida

Compared with other fungi, treatment of candidiasis can be better guided by in vitro susceptibility testing. Because the susceptibilities of Candida spp. in general are predictable based on species identification, it is currently not recommended to routinely test all Candida isolates for susceptibility [230]. Infectious Diseases Society of America (IDSA) guidelines recommend that susceptibility testing is most helpful in treating deep infection due to nonalbicans species of Candida [230]. If the patient has been treated previously with an azole antifungal agent, the possibility of microbiologic resistance must be considered.

Although the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) has established standards for Candida spp., interpretative breakpoints exist only for fluconazole, itraconazole, and voriconazole [231,232,233]. Evidence supporting the association between MIC and clinical outcome for invasive candidal disease is not extensive; for example, fluconazole breakpoints were based predominantly on mucosal candidiasis data. One other limitation of testing for Candida spp. is the variability in interpretating the results (e.g., misinterpretation of trailing growth at high drug concentrations) [234].

Based on in vitro susceptibility testing performed on BSI isolates from around the world, C. albicans, C. tropicalis, and C. parapsilosis are considered to be generally susceptible to current antifungal agents [160,162]. Some strains of C. lusitaniae can be resistant to polyene agents (amphotericin B and nystatin) although they remain susceptible to triazoles (fluconazole, itraconazole, voriconazole, posaconazole, and ravuconazole) [162,235]. C. krusei is intrinsically resistant to fluconazole and often demonstrates decreased susceptibility to amphotericin B and flucytosine, although it remains susceptible to caspofungin, voirconazole, posaconazole, and ravuconazole [118]. C. rugosa has demonstrated decreased susceptibility to amphotericin B, nystatin, and fluconazole [118]. This property and its propensity to colonize skin could help explain how this species has caused several difficult-to-control outbreaks of infection in hospitals [166,167]. C. glabrata has emerged as an important problem, ranking second or third most frequently isolated after C. albicans in some institutions. Although it is generally susceptible to fluconazole, this species can easily develop acquired resistance, particularly in patients who have received prior fluconazole prophylaxis or treatment [158,163].

Outbreaks of Candida

Molecular epidemiology has been instrumental in establishing the gastrointestinal tract as the most important endogenous reservoir for Candida spp. infections [141,236,237,238,239]. Although the majority of episodes of nosocomial candidemia is likely of endogenous origin, outbreaks of Candida spp. infections can occur from exogenous transmission. A wide array of Candida spp. has been implicated as the cause of HAI outbreaks worldwide (Table 43-9). Candida spp. also are able to colonize a variety of fluids, and there have been several reports of transmission via contaminated infusates and biomedical devices (Table 43-9). In many instances, advances in molecular typing have been used to confirm the source of these outbreaks [172,238,239,240,241,242]. However, transmission of Candida spp. from one patient

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to another via the hands of healthcare workers is most commonly reported (Table 43-9). Candida spp. can survive on environmental surfaces and increase the likelihood of cross-transmission.

TABLE 43-9 SELECTED PUBLISHED OUTBREAKS OF NOSOCOMIAL CANDIDA SPP. INFECTIONS

Author (Year, Country) [Ref.] Patient Population No. Primary Site Species Probable Source Control Measures Recommended or Applied ICU, intensive care unit; NICU, neonatal intensive care unit; TPN, total parenteral nutrition; SICU, surgical intensive care unit. Plouffe et al. (1977, US) [296] Surgery 14 Candidemia C. parapsilosis Contaminated IV fluids Vacuum system cleaned Solomon et al. (1984, US) [297] Medicine  5 Candidemia C. parapsilosis Contaminated vacuum pump Use of vacuum pump stopped Burnie et al. (1985, England) [298] ICU 14 Candidemia C. albicans Cross-infection Strict cross-infection control strategies McCray et al. (1986, US) [299] Ophthalmalogy 13 Endopthalmitis C. parapsilosis Contaminated ocular irrigating solution Solution recall Berger et al. (1988, Germany) [300] Hematology 12 Mixed C. krusei Bottle of contaminated lemon juice in hospital kitchen Bottle elimination Vaudry et al. (1988, Canada) [301] NICU  3 Candidemia C. albicans Cross-infection No intervention Isenberg et al. (1989, US) [302] Surgical  8 Sternal wound infections C. tropicalis Scrub nurse Removal from cardiac team Moro et al. (1990, Italy) [303] ICU  8 Candidemia C. albicans Parenteral nutrition Adherence to standard protocols for compounding and administering parenteral nutrition Sherertz et al. (1992, US) [304] NICU  5 Candidemia C albicans(3), Syringe fluids, TPN Single use of syringes         C. tropicalis(1)             C. parapsilosis     Finkelstein et al. (1993, Israel) [305] NICU  6 Candidemia C. tropicalis Cross-infection Strict hand washing and contact isolation of cases Johnston et al. (1994, Canada) [306] Surgery  5 Prosthetic valve endocarditis C. parapsilosis Intraoperative contamination of cardiac bypass equipment Decontamination of equipment Reagan et al. (1995, US) [307] NICU  7 Candidemia C. albicans No specific source Not specified Diekema et al. (1997, US) [308] Surgery  4 Prosthetic valve endocarditis C. parapsilosis Glove tears during surgery Change to more durable gloves D'Antonio et al. (1998, Italy) [309] Hematology/oncology  3 Candidemia C. inconspicua Cross-infection No intervention Huang et al. (1998, Taiwan) [268] NICU  9 Candidemia C. albicans Cross-infection Strict hand washing Levin et al. (1998, Brazil) [269] Oncology  6 Candidemia C. parapsilosis Implantable central venous catheters Improved central venous catheter management Huang et al. (1999, Taiwan) [267] NICU 17 Candidemia C. parapsilosis Cross-infection Strict hand washing with alcoholic chlorhexidine handrub Nedret Koc et al. (2002, Turkey) [310] ID clinic  9 Candidemia C. glabrata Contaminated bottles for milk feed Bottle sterilization process fixed Chowdhary et al. (2003, India) [311] NICU 16 Candidemia C. tropicalis Linens Strict hand washing and contact isolation of cases Colombo et al. (2003, Brazil) [166] Hospital  6 Candidemia C. rugosa Not identified No intervention Barchiesi et al. (2004, Italy) [266] Pediatric oncology   Candidemia C. parapsilosis Cross-infection Not specified Clark et al. (2004, US) [262] Hospital 22 Candidemia C. parapsilosis Multiple Improved hand hygeine Posteraro et al. (2004, Italy) [270] Pediatric oncology  3 Candidemia C parapsilosis Cross-infection No intervention Jang et al. (2005, Korea) [312] SICU 34 Candiduria C. tropicalis Urine disposal route Improvement in urine disposal system

Control and Prevention of Nosocomial Yeast Infections

All of the established risk factors for developing nosocomial bacterial BSIs also apply to candidemia, and established prevention guidelines for preventing BSIs should be applied routinely to prevent candidemia as well (See Chapters 29, 37, 38, 42). CDC's HICPAC has no specific guidelines for candidemia prevention in hospitalized patients except for the approaches outlined in the Guidelines for the Prevention of Intravascular Catheter-Related Infections [243,244]. Regardless, several factors should be considered if a persistent problem with Candida BSIs or other forms of nosocomial candidiasis is detected in a healthcare setting.

Reducing Gastrointestinal Colonization with Candida

Colonization with Candida spp. is the overriding risk factor associated with developing nosocomial candidiasis. Removing the endogenous reservoir should reduce a patient's risk for subsequent disease substantially. Using systemic antifungals (i.e., prophylaxis) before any evidence of active disease is one well-studied method that can accomplish this. Mounting evidence on the efficacy of preventing candidemia in the subset of patients at highest risk for invasive disease has led the HICPAC and IDSA to make specific recommendations for the HSCT and neutropenic population [245,246]. Because candidiasis usually occurs in the period after transplant but before engraftment, fluconazole should be started on the day of HSCT and continued at least until engraftment [245]. The appropriate duration of prophylaxis is not known, but at least one study has shown a survival benefit when prophylaxis is extended for at least 75 days [247,248]. Because autologous recipients generally have a lower risk for invasive fungal infection than allogeneic recipients have, only autologous recipients with particular conditions (underlying hematologic malignancies, prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, and recent treatment with fludarabine or 2-CDA) should receive antifungal prophylaxis [245].

Patients who receive solid organ transplants, especially these undergoing orthotopic liver transplantation, also have been identified as being at high risk for invasive candidiasis [249,250]. Various therapies, including amphotericin B deoxycholate, itraconazole, liposomal amphotericin B, and fluconazole have been studied as prophylactic regimens posttransplantation [246]. At this time, the IDSA recommends that only patients with liver transplant who have ≥2 risk factors for invasive fungal disease [251] receive antifungal prophylaxis during the early postoperative period [230]. Prophylaxis in patients receiving liver transplants who are considered low risk and patients receiving pancreas, small-bowel, or other solid organ transplantations is not currently recommended [230].

Prophylaxis could be warranted in ICU patients with high incidence of invasive candidiasis when aggressive

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infection-control procedures are failing to reduce rates [230,252,253]. The use of prophylaxis in ICU patients with only low risks of candidiasis could be inappropriate due to the increased risk of adverse drug events and selection of resistant organisms [254]. For example, infections with Candida spp. exhibiting reduced susceptibility to fluconazole (e.g., C. glabrata or C. krusei) could increase as a consequence of the introduction of fluconazole prophylaxis [194,255,256].

A patient population in which the role of antifungal prophylaxis is under increasing study is the neonatal ICU population, specifically extremely low-birth-weight infants (<1,000 grams). Although several studies have documented decreased rates of infection with antifungal prophylaxis [257,258,259,260], no consensus on the specific subset of patients in which this approach should be used [261] exists among practitioners. Fewer studies have evaluated this approach in surgical ICU patients. A recent meta-analysis evaluating these studies determined no overall survival benefit among treated patients compared with untreated patients [256].

Preventing Cross-Transmission of Yeast

Currently, standard precautions should be used for all patients with candidemia [243]. Although transmission via healthcare workers' hands could be the pathway for some acquisition of Candida spp., most candidemia is thought to be derived from the patient's own flora, so enhanced precautions to prevent person-to-person spread are not justified. Local authorities' identification of an organism of epidemiologic concern (e.g., a particular Candida spp. of high virulence or resistance) could justify contact precautions. However, outbreaks of candidemia involving cross-transmission have been associated with sub standard hand hygiene and have been interrupted by improved compliance with standard precautions [262]. Efforts to improve hand hygiene, such as those described in HICPAC guidelines [244], therefore, are relevant to preventing and controlling candidemia. Use of waterless antiseptic agents (e.g., alcohol-based solutions) has gained acceptance, and studies have shown that alcohol-based hand washes are effective against Candida spp. [158,263], but efficacy can vary based on the concentration of alcohol in the products, amount of contact time, and burden of yeast present [264,265]. Other hand-hygiene antiseptic agents (e.g., chlorhexidine [2% and 4% aqueous], iodine compounds, iodophors, and phenol derivatives) also have activity against fungi [244].

Molecular Typing of Yeast

Molecular epidemiology has proven useful for implicating the gastrointestinal tract as the most important endogenous reservoir for Candida spp. infections [141,236,237,238,239] documenting transmission via hands of healthcare workers [262,266,267,268,269,270] and for confirming the source (e.g., contaminated infusates, biomedical devices) during outbreak investigations [172,238,239,240,241,242]. In addition, molecular typing methods have documented that strains of Candida spp. surviving on environmental surfaces within the hospital can be acquired by patients there [172,271].

Molecular typing methods are rapidly evolving. A variety of methods has been described in detail elsewhere [272,273]. Techniques used in the past include those based on RFLP with Southern blot hybridization, electrophoretic karyotyping, multilocus enzyme electrophoresis, and PCR-based techniques (e.g., random amplified polymorphic DNA). Newer techniques such as multilocus sequence typing (MLST) and microsatellite typing have performed at least comparably to other established DNA fingerprinting techniques for C. albicans[274,275,276]. MLST is emerging as a powerful tool for subtyping C. albicans because it has a high degree of resolution, can characterize large numbers of isolates rapidly, and does not require subjective interpretation of banding patterns [274,275,276]. MLST also is available for C. glabrata and C. tropicalis. Other methods, including use of microarrays, which offer the hope of reproducible, high throughput typing, are under development.

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